From the FDA cover letter: “Afoxolaner and sarolaner are approved for oral use in dogs only. Fluralaner is approved for both oral use in dogs only and topical use in dogs and cats only. For the time period of the ADE database search (5/3/2017 through 9/30/2017), there were a total of 2243 ADE reports received for afoxolaner for dogs, a total of 3697 ADE reports received for fluralaner for dogs, and a total of 1126 ADE reports received for sarolaner for dogs.”

A reminder about how to use these reports (verbatim from the FDA cover letter):

“More than one clinical sign may have been reported per ADE case report, so the ‘Number of times reported’ column is not additive and does not necessarily represent the total number of reports received. Also, if a manufacturer reports multiple products in a single ADE case report, clinical signs are associated with each of the manufacturer’s products.”

For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes. The clinical detail listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.

The accuracy of information regarding the ADE is dependent on the quality of information received from the reporting veterinarian or animal owner.

Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk, because there is no accurate way to determine how many animals were actually given the drug, which is needed as the denominator in calculations of incidence and relative risk.

It is inappropriate to make use of adverse event data to compare the safety of different products. For example, if a drug is widely used to treat certain conditions, there may be more ADEs for that drug than another product that is not used as often. This would not mean that the first drug was more unsafe than the second. The number of reports simply represents the number of ADEs received for a particular drug and should not be used for any type of comparison purposes.

Underreporting occurs with most adverse event reporting systems. The frequency of reporting for a given drug product varies over time, and may be greater when the drug is newly marketed, or when media publicity occurs.

Information on how the drugs were used (for indications on the product label or in an extra label manner) is not provided in the clinical detail listing.”

I have received Adverse Drug Event Reports from FDA for Bravecto, Nexgard, and Simparica, encompassing dates 1/28/2017 – 5/2/2017. Below is a reminder about how to read and use these reports; this is text taken verbatim from the beginning of the report.

For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes. The clinical detail listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.

The accuracy of information regarding the ADE is dependent on the quality of information received from the reporting veterinarian or animal owner.

Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk, because there is no accurate way to determine how many animals were actually given the drug, which is needed as the denominator in calculations of incidence and relative risk.

It is inappropriate to make use of adverse event data to compare the safety of different products. For example, if a drug is widely used to treat certain conditions, there may be more ADEs for that drug than another product that is not used as often. This would not mean that the first drug was more unsafe than the second. The number of reports simply represents the number of ADEs received for a particular drug and should not be used for any type of comparison purposes.

Underreporting occurs with most adverse event reporting systems. The frequency of reporting for a given drug product varies over time, and may be greater when the drug is newly marketed, or when media publicity occurs.

Information on how the drugs were used (for indications on the product label or in an extra label manner) is not provided in the clinical detail listing.

Bravecto (fluralaner) ADE Report

For this time period, there were 1,907 reports, including 1,681 for dog, 196 for cat, and 29 for human (accidental) exposure. The top 6 reported clinical signs for dogs consuming the oral product are:

Vomiting and Emesis (743)

Lethargy (135)

Diarrhea/Loose Stool/bloody diarrhea (131)

Anorexia/decreased appetite/not eating/inappetance (108)

Lack of efficacy (ectoparasites) (98)

Seizure (63)

Deaths reported total 51 (death + death by euthanasia + found dead + sudden death + unexplained death). The Bravecto product insert lists vomiting, decreased appetite, diarrhea, and lethargy as the top 4 clinical signs seen in the pre-approval field study (224 dogs treated with fluralaner).

For cats (topical application of fluralaner), the top 6 reported clinicals signs are:

New in this report are adverse events related to topical use of Bravecto on dogs. Numbers reported are low due to recent release of the topical for dogs. Adverse event categories include ineffectiveness (flea), abnormal test results, alopecia, decreased appetite, diarrhea, lethargy, moist dermatitis, and vomiting.

Nexgard (afoxolaner) ADE Report

For this time period, there were 725 reports, including 720 for dog, 1 for cat, and 4 for human (accidental) exposure. The top 6 reported clinical signs are:

Vomiting/Emesis/Haematemesis (217)

Lethargy (132)

Pruritus/itching (103)

Diarrhea/Loose Stool/Bloody Diarrhea (88)

Anorexia/Not eating/Inappetance (72)

Seizure (41)

Deaths reported total 21 (death + death by euthanasia).

The Nexgard product insert lists vomiting (with and without blood), dry flaky skin, diarrhea (with and without blood), lethargy, and anorexia as the top 5 adverse events in the pre-approval field study (415 dogs treated with afoxolaner). The product insert also contains a caution about use in dogs with a history of seizures.

Simparica (sarolaner) ADE Report

In the U.S., Simparica received FDA approval on February 25, 2016, and this is the fourth ADE report I have requested for this drug. For this time period, there were 102 reports, including 98 for dog, 4 for cat, and 0 for human (accidental) exposure. The top 6 clinical signs reported are:

Vomiting (75)

Seizure (48)

Lethargy (33)

Diarrhea/Loose Stool/Bloody Diarrhea (37)

Tremor (30)

Ataxia (20)

Deaths reported total 7 (death + death by euthanasia).

The Simparica product insert lists vomiting, diarrhea, lethargy, and inappetance as the top 4 clinical signs in the U.S. field study (315 dogs treated with Simparica). The insert also states “Simparica may cause abnormal neurologic signs such as tremors, decreased conscious proprioception, ataxia, decreased or absent menace, and/or seizures.”

I want to share a link to a recent news report about Bravecto, to which I contributed. I agreed to be interviewed for this story for one reason: I continue to search for someone in the scientific community with the knowledge and facilities to help me investigate why this drug causes side effects in some animals. Before anyone jumps in saying “there are no side effects with Bravecto,” please keep in mind that even the manufacturer lists side effects on the product insert. I believe if we can understand the mechanism, we can make the use of the drug safer. At present, with thousands of doses administered to dogs (and now cats) around the world every month, doesn’t it make sense to improve our understanding of how the drug impacts the dog or cat’s body? Let us keep in mind that this class of drugs (isoxazolines) has been in use in dogs around the world for just over 2 years.

Two important points to keep in mind if you watch the video:

I. The manufacturer states the incidence of reported side effects is very low. However, this figure depends entirely on how many people actually file a report.

II. Many people are clamoring for proof. “Show me proof that Bravecto killed a dog.” Well, we can’t because there is no pre- or post-mortem test to do so. I have read at least a dozen necropsy reports in the past year. I’ve reached out to some of the pathologists who wrote the reports. I’ve communicated with a veterinary pharmacologist and a veterinary toxicologist. Not one of these professionals has yet been able to answer questions about “proof.”

I know there are many strong feelings about all of this, on both sides of the aisle. You are welcome to comment but I would ask that everyone keep it civil. If anyone has a background in mammalian pharmacology/toxicology and a laboratory and wants to work with me, please contact me!

I have received Adverse Drug Event Reports from FDA for Bravecto, Nexgard, and Simparica, encompassing dates 7/1/2016 – 10/15/2016. Below is a reminder about how to read and use these reports; this is text taken verbatim from the beginning of the report.

For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes. The clinical detail listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.

The accuracy of information regarding the ADE is dependent on the quality of information received from the reporting veterinarian or animal owner.

Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk, because there is no accurate way to determine how many animals were actually given the drug, which is needed as the denominator in calculations of incidence and relative risk.

It is inappropriate to make use of adverse event data to compare the safety of different products. For example, if a drug is widely used to treat certain conditions, there may be more ADEs for that drug than another product that is not used as often. This would not mean that the first drug was more unsafe than the second. The number of reports simply represents the number of ADEs received for a particular drug and should not be used for any type of comparison purposes.

Underreporting occurs with most adverse event reporting systems. The frequency of reporting for a given drug product varies over time, and may be greater when the drug is newly marketed, or when media publicity occurs.

Information on how the drugs were used (for indications on the product label or in an extra label manner) is not provided in the clinical detail listing.

Bravecto (fluralaner) Report:

For this time period, there were 1,875 reports, including 1,867 for dog, 4 for cat, and 4 for human (accidental) exposure. The top 6 reported clinical signs are:

The Nexgard product insert lists vomiting (with and without blood), dry flaky skin, diarrhea (with and without blood), lethargy, and anorexia as the top 5 clinical signs in the pre-approval field study. The product insert also contains a caution about use in dogs with a history of seizures.

Simparica (sarolaner) Report:

In the U.S., Simparica received FDA approval on February 25, 2016, and this is the second ADE report I have requested for this drug. For this time period, there were 76 reports, including 75 for dog and 1 for cat exposure. The top 5 clinical signs reported are:

The Simparica product insert lists vomiting, diarrhea, lethargy, and inappetance as the top 4 clinical signs in the U.S. field study (315 dogs treated with Simparica). The insert also states “Simparica may cause abnormal neurologic signs such as tremors, decreased conscious proprioception, ataxia, decreased or absent menace, and/or seizures.”

I have received Adverse Drug Event Reports from FDA for Bravecto, Nexgard, and Simparica, encompassing dates 4/1/2016 – 7/15/2016. Below is a reminder about how to read and use these reports; this is text taken verbatim from the beginning of the report.

For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes. The clinical detail listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.

The accuracy of information regarding the ADE is dependent on the quality of information received from the reporting veterinarian or animal owner.

Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk, because there is no accurate way to determine how many animals were actually given the drug, which is needed as the denominator in calculations of incidence and relative risk.

It is inappropriate to make use of adverse event data to compare the safety of different products. For example, if a drug is widely used to treat certain conditions, there may be more ADEs for that drug than another product that is not used as often. This would not mean that the first drug was more unsafe than the second. The number of reports simply represents the number of ADEs received for a particular drug and should not be used for any type of comparison purposes.

Underreporting occurs with most adverse event reporting systems. The frequency of reporting for a given drug product varies over time, and may be greater when the drug is newly marketed, or when media publicity occurs.

Information on how the drugs were used (for indications on the product label or in an extra label manner) is not provided in the clinical detail listing.

Bravecto (fluralaner) Report:

For this time period, there were 2,338 reports, including 2,335 for dog, 1 for cat, and 2 for human (accidental) exposure. The top 6 reported clinical signs are:

The Nexgard product insert lists vomiting (with and without blood), dry flaky skin, diarrhea (with and without blood), lethargy, and anorexia as the top 5 clinical signs in the pre-approval field study. The product insert also contains a caution about use in dogs with a history of seizures.

Simparica (sarolaner) Report:

In the U.S., Simparica received FDA approval on February 25, 2016, and this is the first ADE report I have requested for this drug. For this time period, there were 27 reports, including 26 for dog and 1 for cat exposure. The top 5 clinical signs reported are:

Vomiting/Emesis 12 reports

Lethargy 8 reports

Diarrhea/Bloody Diarrhea/Loose Stool 8 reports

Twitching/Ataxia/Seizure/Tremor 13 reports

Not Eating/Decreased Appetite/Anorexia 6 reports

There were no deaths reported.

The Simparica product insert lists vomiting, diarrhea, lethargy, and inappetance as the top 4 clinical signs in the U.S. field study (315 dogs treated with Simparica). The insert also states “Simparica may cause abnormal neurologic signs such as tremors, decreased conscious proprioception, ataxia, decreased or absent menace, and/or seizures.”

Today I received an email from Zoetis (formerly Pfizer), promoting the company’s newly approved flea/tick preventive called Simparica. This medication contains the chemical sarolaner, which is closely related to the drugs afoxolaner (Nexgard) and fluralaner (Bravecto). I’ve spent countless hours on my blog responding to comments about Nexgard and Bravecto after I posted about them in November 2014. It is no surprise to me that Zoetis has jumped on this bandwagon. Here’s the lowdown on Simparica, based on the company-provided product insert.

Which Dogs Can Take It?

Dogs must be at least 6 months of age, weighing at least 2.8 pounds. Zoetis has NOT evaluated the use of Simparica in breeding, pregnant, or lactating dogs.

How Do I Give It?

Simparica is given by mouth once a month, with or without food. Chewables are flavored and available in six dosages based on body weight.

Simparica does NOT repel fleas and ticks. In order for them to be exposed to the chemical, they must bite your dog. According to the email I received today, Simparica starts killing ticks in 8 hours and is >96.9% effective for 35 days against weekly reinfestations of the above named ticks. Simparica starts killing fleas within 3 hours and reduced the number of live fleas by >96.2% within 8 hours after flea infestation through Day 35. Note that these numbers are based on well-controlled laboratory studies.

How Does It Work?

Sarolaner is a chemical in the isoxazoline group, which inhibits the function of the neurotransmitter gamma aminobutyric acid (GABA) receptor and glutamate receptor in insects (fleas) and acarines (ticks). This leads to uncontrolled neuromuscular activity leading to death.

Is It Safe?

The US field study included 479 dogs (315 dogs received Simparica and 164 dogs received an active control once monthly for three months). The top adverse reactions were vomiting (0.95%), diarrhea (0.63%), and lethargy (0.32%). One female dog age 8 years was lethargic, ataxic while trying to urinate, had elevated third eyelids, and had loss of appetite one day after taking both Simparica and a heartworm preventative containing ivermectin and pyrantel pamoate.

The margin of safety study included 8-week old Beagle puppies, who received doses of 0, 1x, 3x, and 5x the recommended maximum dose at 28-day intervals for 10 doses (8 dogs per group). The “0” dose group received a placebo. No neurologic signs were seen in the 1x group. Three pups exhibited tremors in the 3x group. In the 5x group, one pup had a seizure on Day 61; one pup had tremors on Day 0 and head incoordination on Day 140; and one pup had seizures after Doses 2 and 4 and tremors after Dose 2 and 3.

FURTHER INVESTIGATION NEEDED!!

I am astounded to read the final paragraph under Animal Safety on the product insert. I’ve included it word-for-word below. For me, these are simply the most intriguing four sentences I have read ALL YEAR.

Why?

Because I believe whatever happened in this dog is the VERY process that is occurring in all of the dogs who’ve experienced side effects with Bravecto and Nexgard. Some of these dogs have died. We must determine what is happening here!

“In a separate exploratory pharmacokinetic study, one female dog dosed at 12 mg/kg (3X the maximum recommended dose) exhibited lethargy, anorexia, and multiple neurological signs including ataxia, tremors, disorientation, hypersalivation, diminished proprioception, and absent menace, approximately 2 days after a third monthly dose. The dog was not treated, and was ultimately euthanized. The first two doses resulted in plasma concentrations that were consistent with those of the other dogs in the treatment group. Starting at 7 hours after the third dose, there was a rapid 2.5 fold increase in plasma concentrations within 41 hours, resulting in a Cmax more than 7-fold higher than the mean Cmax at the maximum recommended use dose. No cause for the sudden increase in sarolaner plasma concentrations was identified.“

I am so pleased to say that my 01/06/16 FOIA request for Bravecto/Nexgard Adverse Drug Event reports has been fulfilled! This is record timing compared to the last request, which took 5 months. As anticipated, there were a large number of reports during the time period encompassing 06/18/15 – 01/06/16, as follows:

Afoxolaner (Nexgard): 2,048 reports

Fluralaner (Bravecto): 2,852 reports

This is compared to the previous report I received in November 2015, encompassing 1/1/13 – 06/17/15:

Afoxolaner (Nexgard): 5,087

Fluralaner (Bravecto): 2,467

I’d like to gently remind you of the following points as you read these reports. This information is taken from the first two pages, and it’s important to view all of this data with these things in mind.

The Center for Veterinary Medicine (CVM) states “The primary purpose for maintaining the CVM ADE database is to provide an early warning or signaling system to CVM for adverse effects not detected during pre-market testing of FDA approved animal drugs and for monitoring the performance of drugs not approved for use in animals. CVM’s ADE reporting system depends on detection and voluntary reporting of adverse clinical events by veterinarians and animal owners.”

“Clinical signs reported for an active ingredient are listed in order from most frequently reported to least frequently reported, grouped by species and route of administration.”

“More than one clinical sign may have been reported per ADE case report, so the ‘Number of times reported’ column is not additive and does not necessarily represent the total number of reports received.”

“For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes. The clinical detail listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.”

“The accuracy of information regarding the ADE is dependent on the quality of information received from the reporting veterinarian or animal owner.”

“Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk, because there is no accurate way to determine how many animals were given the drug, which is needed as the denominator in calculations of incidence and relative risk.”

“It is inappropriate to make use of adverse event data to compare the safety of different products. For example, if a drug is widely used to treat certain conditions, there may be more ADEs for that drug than another product that is not used as often. This would not mean that the first drug was more unsafe than the second.”

“Underreporting occurs with most adverse event reporting systems. The frequency of reporting for a given drug product varies over time, and may be greater when the drug is newly marketed, or when media publicity occurs.”

I have finally received the Bravecto and Nexgard Adverse Drug Event (ADE) reports from FDA! I made a Freedom of Information Act request for these reports on June 17, 2015, after hearing from so many of you whose dogs experienced side effects after taking these drugs. I wanted to see what adverse events had been reported to the manufacturers and FDA, since our experience with these drugs is quite limited.

Both reports contain information for the time period 1/1/2013 – 06/17/2015. For this time period, there were a total of 5,087 ADE reports received for afoxolaner (Nexgard) for dogs, and a total of 2,467 ADE reports received for fluralaner (Bravecto) for dogs.

Before you delve into the reports, here is some important information. This is all included in the first two pages of the reports, but I want to highlight it here:

The Center for Veterinary Medicine (CVM) states “The primary purpose for maintaining the CVM ADE database is to provide an early warning or signaling system to CVM for adverse effects not detected during pre-market testing of FDA approved animal drugs and for monitoring the performance of drugs not approved for use in animals. CVM’s ADE reporting system depends on detection and voluntary reporting of adverse clinical events by veterinarians and animal owners.”

“Clinical signs reported for an active ingredient are listed in order from most frequently reported to least frequently reported, grouped by species and route of administration.”

“More than one clinical sign may have been reported per ADE case report, so the ‘Number of times reported’ column is not additive and does not necessarily represent the total number of reports received.”

“For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes. The clinical detail listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.”

“The accuracy of information regarding the ADE is dependent on the quality of information received from the reporting veterinarian or animal owner.”

“Accumulated ADE reports should not be used to calculate incidence rates or estimates of drug risk, because there is no accurate way to determine how many animals were given the drug, which is needed as the denominator in calculations of incidence and relative risk.”

“It is inappropriate to make use of adverse event data to compare the safety of different products. For example, if a drug is widely used to treat certain conditions, there may be more ADEs for that drug than another product that is not used as often. This would not mean that the first drug was more unsafe than the second.”

“Underreporting occurs with most adverse event reporting systems. The frequency of reporting for a given drug product varies over time, and may be greater when the drug is newly marketed, or when media publicity occurs.”

What’s Next?

I plan to sift through both reports and group the adverse events by organ system. I’ll write another post when I’ve completed this task. I continue to hear from dog owners whose dogs 1) have had no apparent side effects, and 2) have had side effects ranging from mild and self-limiting to severe, debilitating, and even deadly. My message to everyone is to report anything amiss, even if it seems small. As mentioned above, the CVM uses the database to monitor drugs after they’ve been approved. This is the only official channel to impact whether a drug stays on the market or not. If your dog is having issues and you need help with reporting and support from other folks who’ve been down the same road, head over to Facebook to the Nexgard and Bravecto groups.

I don’t know about you, but this photo gives me the willies. This is a dog’s fur. The little black specks are flea dirt. Flea dirt is a nice way of saying flea poop. Flea poop contains blood. You can prove this to yourself by placing a few specks on a wet paper towel, which will turn reddish-orange due to the blood. Gross, right? And very uncomfortable for your dog. Not to mention that in the worst flea infestations, a dog can actually become anemic due to these blood-sucking parasites. What’s a dog lover to do? [Read more…]